An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases

Abstract

The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches.

Keywords: aHUS; cilia; ciliopathies; nephrotic syndrome; podocyte; polycystic kidney disease.

Figure 1

(A) Podocyte-specific inducible and mosaic change of expression of membrane-tagged fluorescent proteins proves interdigitation of neighboring podocytes. Induction results in the expression of green fluorescent protein while non-induced cells express a bright red fluorescent protein. Podocytes expressing the different types of fluorescent reporter interdigitate and closely enwrap the glomerular capillaries. (B) Electron microscopy of the three layers of the glomerular filtration barrier (EC, endothelial cell; GBM, glomerular basement membrane; P, podocyte; FP, foot process; SD, slit diaphragm). (C) In a podocyte-specific proteinuric knockout mouse model secondary foot processes lose their structure and show effacement, a structural change also observed in multiple human proteinuric disorders.

Figure 2

(A) Cystic phenotype in a mouse model of ciliary dysfunction. (B) Immunofluorescence staining of cilia (acetylated tubulin) and the ciliary base (pericentrin) in human epithelial cells in cell culture. (C) Schematic illustration of the involvement of cilia in the regulation of intracellular signaling pathways.